Discovery of a simplified deguelin analog as an HSP90 C-terminal inhibitor for HER2-positive breast cancer

A series of O-substituted analogs of the C-ring-truncated scaffold of deguelin designed as heat shock protein 90 (HSP90) C-terminal inhibitors were investigated as novel antitumor agents against human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Among the synthesized compounds, compound 37 displayed significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells with little cytotoxicity to normal cells. Mechanistic studies of compound 37 carried out by HSP90 alpha C-terminal inhibitor screening, the induction of the heat shock response and downregulation of HSP90 client proteins indicated that the antitumor activity of 37 in breast cancer cells could be attributed to the destabilization and inactivation of HSP90 client proteins by the binding of 37 to the C-terminal domain of HSP90. A molecular docking study of compound 37 with a HSP90 homology model indicated that its S-isomer fit well in the ATP binding site of the Cterminal domain, forming key interactions.

Automated summary

The investigation showed that compound 37, designed as a HSP90 C-terminal inhibitor, displayed significant antitumor activity against HER2-positive breast cancer cells by destabilizing and inactivating HSP90 client proteins through binding to the C-terminal domain of HSP90.